Herpes zoster mRNA vaccine induces superior vaccine immunity over licensed vaccine in mice and rhesus macaques

ABSTRACT

Herpes zoster remains an important global health issue and mainly occurs in aged and immunocompromised individuals with an early exposure history to Varicella Zoster Virus (VZV). Although the licensed vaccine Shingrix has remarkably high efficacy, undesired reactogenicity and increasing global demand causing vaccine shortage urged the development of improved or novel VZV vaccines. In this study, we developed a novel VZV mRNA vaccine candidate (named as ZOSAL) containing sequence-optimized mRNAs encoding full-length glycoprotein E encapsulated in an ionizable lipid nanoparticle. In mice and rhesus macaques, ZOSAL demonstrated superior immunogenicity and safety in multiple aspects over Shingrix, especially in the induction of strong T-cell immunity. Transcriptomic analysis revealed that both ZOSAL and Shingrix could robustly activate innate immune compartments, especially Type-I IFN signalling and antigen processing/presentation. Multivariate correlation analysis further identified several early factors of innate compartments that can predict the magnitude of T-cell responses, which further increased our understanding of the mode of action of two different VZV vaccine modalities. Collectively, our data demonstrated the superiority of VZV mRNA vaccine over licensed subunit vaccine. The mRNA platform therefore holds prospects for further investigations in next-generation VZV vaccine development.

KEYWORDS:

• Varicella Zoster Virus
• mRNA vaccine
• Shingrix
• nonhuman primate
• immune mechanisms

Acknowledgements

The authors thank Min-Hui Sun, Qin-Sheng Dai, and Jia Li for technical support from the Target Discovery Center of China Pharmaceutical University, and also thank the Core Facility of Shandong University for instrumental and technical support on this study. The authors also thank Firestone Biotechnology (Shanghai) for technical assistance in the development of novel ionizable lipids and thank Baidu, Inc. for authorizing Dr. Lin’s lab to use the LinearDesign Algorithm freely for commercial and non-commercial purposes in this study. The authors thank Dr. Liang Zhang for running the LinearDesign Algorithm (Baidu) to codon-optimize the mRNA sequence.

Disclosure statement

No potential conflict of interest was reported by the authors.

Data availability statement

All data are available upon reasonable request to the corresponding authors.

Additional information

Funding

This work was supported by Natural Science Foundation of Jiangsu Province: [Grant Number BK20221031]; National Natural Science Foundation of China: [Grant Number 32200764]; Fundamental Research Funds for the Central Universities: [Grant Number 2632022YC01]; Natural Science Foundation of Shandong Province: [Grant Number ZR2023YQ066]; the Open Project of State Key Laboratory of Natural Medicines: [Grant Number SKLNMKF202309]; the State Key Laboratory of Microbial Technology Open Projects Fund: [Grant Number M2023-13].